3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and method of preparation



United States Patent ()fiice 3,364,228 Patented Jan. 16, 1968 3HYDROXYMETHYL 4 (INDOL 3 YL) HEXA- HYDRO 1H AZEPINES AND METHOD OFPREPARATION Jackson B. Hester, In, Portage, Mich., assignor to TheUpjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing.Filed June 22, 1965, Ser. No. 466,101

5 ClaimsKCl. Mil-326.15)

This invention relates to novel3-hydroxymethyl-4-(indol-3-yl)-hexah,ydro-lH-azepines and to processesfor making the same.

The novel 3-hydroxymethyl-4-(indol-3-yl)-hexahydrolH-azepines of thepresent invention can be represented by the following formula:

l ds I wherein R, R and R are hydrogen or alkyl of not more than 4carbon atoms, and R is hydrogen, alkyl of not more than 4 carbon atoms,alkoxy of not more than 4 carbon atoms, or halogen. Examples of alkyl ofnot more than 4 carbon atoms are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, secondary butyl, and tertiary butyl. Examples of alkoxyare methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondarybutoxy, and tertiary butoxy. Examples of halogen are fluoro, chloro, andbromo.

The novel compounds of the invention are nitrogenous bases and, as such,can exist in the protonated and nonprotonated forms according to the pHof the environment. When R is alkyl the nonprotonated form can beoxidized, with hydrogen peroxide, for example, to form the N- oxide. TheN-oxide can exist in both the protonated and nonprotonated formsaccording to the pH of the environment. The protonated forms can beisolated as acid addition salts which are useful in upgrading the freebase and the free base N-oxide forms, that is, the nonprotonated forms.Suitable acids for this purpose include hydrochloric acid, sulfuricacid, phosphoric acid, thiocyanic acid, fluosilicic acid, picric acid,Reineckes acid, azobenzenesulfonic acid, palmitic acid, acetic acid,maleic acid, and cyclohexanesulfamic acid. The acid addition salt can beformed by neutralizing the free base or free base N-oxide with theappropriate acid or by metathesis of a simple acid addition salt such asthe hydrochloride or sulfate with another salt of the desired acid. Thenovel compounds of the invention are useful intermediates, thus, thecondensation products obtained from thiocyanic acid addition salts andformaldehyde, according to U.S. Patents 2,425,320 and 2,606,155, areuseful as pickling inhibitors, and the fluosilicic acid addition saltsare useful as mothproofing agents according to U.S. Patents 1,915,334and 2,075,359.

Novel compounds of the invention wherein R is alkyl can also exist inthe form of quaternary ammonium salts such, for example, as thoseobtained by coordinating the free base form with a loweralkyl halide,for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, andoctyl chloride, bromide, or iodide, including the isomeric formsthereof. The quaternary ammonium salts are useful for forming thecorresponding quaternary ammonium fluosilicic acid salts which areuseful as mothproofing agents. These fluosilicic acid salts can beformed by metathesis of a quaternary ammonium salt with an inorganicflu-osilicate or by liberating the free base, that is, the quaternaryammonium hydroxide (by treating the quaternary ammonium salt with anequivalent of base, for example, sodium hydroxide) and neutralizing withfluosilicic acid. Higher quaternary ammonium salts, as are obtained asdescribed above by using alkyl halides up to 18 carbon atoms, forexample, where the alkyl group is nonyl, decyl, dodecyl, tridecyl,tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, and theisomeric forms thereof, are surface-active compounds useful as wettingagents and as disinfectants.

The compounds of the invention can be prepared by reducing with lithiumaluminum hydride a compound of the following formula:

0 I N R1000 4 R3 II wherein R, R R and R are as given above, and R isalkyl, for example, methyl, ethyl, propyl, butyl, and the isomeric formsthereof. The lithium aluminum hydride reduction can be effected in themanner already known in the art using, for example, ether, dioxane, ortetrahydrofuran as an inert solvent.

The starting compounds or intermediates of Formula II can be prepared byreacting with dialkyl malonate, for example, diethyl malonate, acompound of the following formula:

B. T R4 R3 III wherein R, R R and R are as given above. The reaction iscarried out in the presence of a strong base, for example, sodiumhydroxide, and in an inert solvent, for example, xylene. Other suitablestrong bases include sodium, sodium hydride, and potassium hydroxide.Other suitable inert solvents include toluene, chlorobenzene, anddecahydronaphthalene. The reaction mixture can be worked up for therecovery of the product by neutralization of the base followed bysolvent extraction and/or chromatography and like methods already knownin the art. In some instances, two isomeric forms of the compounds ofFormula II are obtained. These isomers can be separated bychromatography and/or fractional crystallization, if desired, and bothisomers on reduction with lithium aluminum hydride yield compounds ofthe invention. It is not necessary, however, to effect a separationbecause mixtures of the two isomers as crude reaction products can bereduced with lithium aluminum hydride to give the compounds of theinvention.

The starting 3-(2-pyrrolidinyl)indoles of Formula III can be prepared byprocesses already known in the art, for example, Youngdale et al., J.Med. Chem, 7, 415 (1964).

Typical 3-(2-pyrrolidinyl)indoles which can be thus prepared and whichcan be used as starting compounds for the process of the inventioninclude 3-(2-pyrrolidinyl) indole, 1-methyl-3-(2-pyrrolidinyl)indole,3-(1-methyl-2- pyrrolidinyl)indole, 3-(1-ethyl 2-pyrrolidiny1)indole, 1-methyl-3- l-methyl-2-pyrrolidinyl) indole, 5 -methyl-3-( 1-methyl-Z-pyrrolidinyl)indole, 7-methyl-3-(1-methyl-2-pyrrolidinyl)indole, 5 methoxy-3-(l-methyl-2-pyrrolidinyl)indole, 4 chloro-3-(1-methyl-2-pyrrolidinyl)indole, 5-

3 chloro-3-(1-methyl-2-pyrrolidinyl)indole, -bromo-3-(1-methyl-Z-pyrrolidinyl)indole, and 5-fluoro-3-(l-methyl-2-pyrrolidinyl)indole. By use of appropriate starting indoles in theprocesses of Youngdale et al., supra, other starting compounds ofFormula III are readily obtained.

The following example is given by way of illustration, it beingunderstood that the 3-(l-methyl-Z-pyrrolidinyl) indole can besubstituted by any of the 3-(2-pyrrolidinyl) indoles embraced in FormulaIII, e.g., those given above. It is to be understood also that thediethyl malonate can be substituted by other dialkyl malonates, forexample, dimethyl, dipropyl, diisopropyl, dibutyl, diisobutyl,disec.butyl, and di-tert.butyl malonates.

Example1.-3-l1ydr0xymethyl-4-(ina'0le-3-yl)-1-methylhexahydro-IH-azepine (A)Ethyl 1-methyl-2-oxo-4-(indol-3-yl)-hexahydro- 1H-azepine-3-carboxylateLN EtOOC J I? CHa(COOEt)g NaOH T H on. l H H A mixture of3-(l-methyl-Z-pyrrolidinyl)indole (50 g.; 0.25 mole), diethyl malonate(42 g.; 0.262 mole), powdered sodium hydroxide (1.0 g.) and xylene (300ml.) was allowed to reflux under nitrogen for 31.25 hours. During thisperiod ethanol, formed in the reaction, was removed by distillation.Additional 500-mg. portions of powdered sodium hydroxide were added tothe reaction mixture after the reaction had proceeded for 7.5 hours and25.5 hours. The cooled reaction mixture was poured into dilute aceticacid and the mixture was extracted with chloroform. The extract waswashed successively with water, dilute ammonium hydroxide, and saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The last traces of xylene wereremoved from the residue by azeotropic distillation, first with tolueneand then benzene. A benzene solution of the resulting brown oil wasadsorbed on 2 pounds of neutral alumina and chromatographed. Withbenzene 4.006 g. of indole, M.P. 5154 C., was eluted. Elution of thecolumn with 50% ether-chloroform followed by ethyl acetatecrystallization yielded 11.132 g. of ethyl 1methyl-2-oxo-4-(indol-3-yl)hexahydro-1H- azepine-3-carboxylate (isomerA); M.P. 191-195" C. A sample of this material was recrystallizedseveral times from methanol-ethyl acetate for analysis; M.P. 1965-- 198C. The ultraviolet spectrum (ethanol) had A max. 220, 281.5, and 290 m(6 35,750, 5,950, and 5,150, respectively) with an inflection at 275 mu(6 5,550). The infrared spectrum (mineral oil) showed NH: 390 cm." and C0: 1740 and 1627 CHIS-1.

Analysis.-Calcd. for C H N O C, 68.77; H, 7.05; N, 8.91. Found: C,68.36; H, 7.13; N, 8.98.

Concentration of the mother liquors from the above crystallizationsyielded a brown oil (9.09 g.) which had practically the same infraredspectrum as the above crystalline product. An ice-cold solution of thismaterial in 150 ml. of absolute methanol was treated with 30 m1. of0.976 N aqueous sodium hydroxide. The resulting solution was allowed towarm to about 25 C. After a few hours a crystalline precipitate formed.After 24 hours standing, water was added to the mixture which was thenconcentrated to remove the methanol. The solid which remained wascollected by filtration, washed with water, and dissolved in methylenechloride. The methylene chloride solution was washed with Water, driedover anhydrous sodium sulfate, and concentrated in vacuo.Crystallization of the residue from methanol-ethyl acetate yielded threecrops: 2.888 g., M.P. 2095-2125 C.; 0.623

g., M.P. 202.5205 C.; and 0.132 g., M.P. 194198 C. An analytical sampleof ethyl 1-methyl2-oxo-4-(indol-3- yl)hexahydro-1H-azepine-3-carboxylate (isomer B), M.P. 212.5214.5 C., wasprepared by recrystallizing the first crop from methylenechloride-methanol. The ultraviolet spectrum (methanol) had A max. 221,281, and 290 my. (5 37,100, 6,150, and 5,350, respectively) with aninflection at 274 m (6 5,700). The infrared spectrum (chloroform andmineral oil) was almost identical to that of isomer A. A mixed meltingpoint with isomer A was taken; M.P. 20l212.5 C.

Analysis.--Calcd. for C H N O C, 68.77; H, 7.05; N, 8.91. Found: C,68.75; H, 7.18; N, 8.92.

(B) 3 hydroxymethyl 4-(indol-3-yl)-1-methylhexahydro-lH-azepine OCH:

To a stirred, ice-cold suspension of 5.15 g. of lithium aluminum hydridein 500 ml. of dry tetrahydrofuran was added, under nitrogen, 5.0 g.(15.9 mmoles) of the lactamester of Part A (isomer A, M.P. 197-198 C.).This mixture was allowed to reflux gently for 4.75 hours and stand for18 hours at about 25 C. It was then cooled in an ice bath and treatedsuccessively with 5 ml. of water, 5 ml. of 15% aqueous sodium hydroxide,and 15 ml. of water. The inorganic precipitate was collected byfiltration and washed with ether. Concentration of the combined filtrateand washing yielded a solid which was dissolved in ethyl acetate,decolorized with activated carbon, and crystallized to yield3-hydroXymethyl-4-(indol-3- yl)l-methylhexahydro-lH-azepine in twocrops: 3.047 g., M.P. 143.5145.5 C., and 0.272 g., M.P. 143.5- 145.5 C.(80.7% yield). The analytical sample, M.P. 143145 C., was prepared byrecrystallizing some of this material three times from methanol-ethylacetate. The ultraviolet spectrum (ethanol) had max. 223, 282, and 290.5my. (6 34,950, 5,700, and 5,000, respectively) with an inflection at 276my. (6 5,300).

Analysis.-Calcd. for C H N O: C, 74.38; H, 8.58; N, 10.84. Found: C,74.18; H, 8.37; N, 10.53.

I claim:

1. A member of the group consisting of compounds of the followingformula:

HOCH: ,l,

wherein R, R and R are members of the group consisting of hydrogen andalkyl of not more than 4 carbon atoms, and R is a member of the groupconsisting of hydrogen, alkyl of not more than 4 carbon atoms, alkoxy ofnot more than 4 carbon atoms, and halogen, and the acid addition saltsthereof, the N-oxides thereof where R is alkyl and the acid additionsalts thereof, and the alkyl quaternary ammonium salts thereof where Ris alkyl.

2. A compound of the following formula:

wherein R, R and R are hydrogen or alkyl of not more than 4 carbonatoms, and R is hydrogen, alkyl of not more than 4 carbon atoms, alkoxyof not more than 4 carbon atoms, or halogen.

3. 3-hydroxymethy1-4-(indol-3-yl)-1-methylhexahydrolH-azepine.

4. Process for making compounds of the following formula:

5 HOCH N wherein R, R and R are hydrogen or alkyl of not more than 4carbon atoms, and R is hydrogen, alkyl of not more than 4 carbon atoms,alkoxy of not more than 4 carbon atoms, or halogen, which comprisesreacting with 6 a dialkyl malonate in the presence or a strong base acompound having the following formula:

wherein R, R R and R are as given above, and R is alkyl, and reducingthe resulting compound with lithium aluminum hydride.

5. The process of making compounds of Formula I wherein R, R and R arehydrogen or alkyl of not more than 4 carbon atoms, and R is hydrogen,alkyl of not more than 4 carbon atoms, alkoxy of not more than 4 carbonatoms, or halogen, which comprises reducing with lithium aluminumhydride a compound of the Formula II wherein R, R R and R are as givenabove, and R is alkyl.

References Cited UNITED STATES PATENTS 3,214,438 10/1965 Youngdale26-0326.15

ALEX MAZEL, Primary Examiner.

I. A. NARCAVAGE, Assistant Examiner.

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FOLLOWINGFORMULA:
 4. PROCESS FOR MAKING COMPOUNDS OF THE FOLLOWING FORMULA: